Blog | July 19, 2023

DEL Technology and Targeted Protein Degradation Discovery

glu-protac

Targeted protein degradation (TPD) is a rapidly growing field that aims to selectively eliminate disease-causing proteins.1,2 Proteolysis targeting chimeras (PTCs) and molecular glues (MGs) are two promising approaches in this space that leverage the ubiquitin-proteasome system.3 These technologies have the potential to tackle historically challenging proteins that were previously undruggable.  

PTCs are bifunctional molecules that recruit ligase enzymes to target proteins, leading to their ubiquitination and subsequent degradation by the proteasome.4 The advantage they offer is their ability to target proteins that are difficult or impossible to inhibit directly.5 In contrast, MGs act as mediators between target proteins and enzymes, inducing the formation of ternary complexes that lead to protein degradation.1 What they have in common is that both take advantage of proximity-dependent effects to achieve TPD. 

X-Chem’s DNA-encoded library (DEL) technology is the perfect platform for PTC development because it takes advantage of the ubiquitin-proteasome system’s dependency on binding affinity.1,3 DEL-derived ligands can be easily converted into PTCs to drug difficult undruggable proteins. X-Chem’s scientists have already demonstrated the selection of MGs using a dual target selection protocol, and we’ve confirmed ternary binding using advanced analytical techniques. 

Our industry-leading DEL screening platform is opening new avenues for our partners in TPD drug development. Add our medicinal chemistry expertise, and the possibilities for the expedited development of highly specific TPD-based therapeutic candidates over the coming years is truly exponential. 

The Power of Proteolysis Targeting Chimeras in Drug Discovery 

PTCs have revolutionized TPD research, though identifying E3 ligases that can induce TPD presents a challenge that has limited the scope of their use in the past.1,3 This is where X-Chem excels. Our scientists have discovered novel E3 ligands for our partners, enabling the development of TPD-based therapeutic candidates that include potential cancer and autoimmune treatments. 

Another advantage of PTCs is prolonged target engagement with a single dose.1 Traditional small molecule inhibitors typically require continuous dosing to maintain inhibition, whereas PTCs can sustain target degradation. Combined with their demonstrated effectiveness in degrading a variety of difficult-to-inhibit proteins, they are an extremely attractive and increasingly popular option for drug development.5 

The Promise of Molecular Glues in Precision Medicine 

Molecular glues are another class of bifunctional protein degraders that have emerged as a promising tool in precision medicine. Unlike PTCs, which recruit E3 ligases to induce target protein degradation, MGs act as mediators between target proteins and enzymes, inducing the formation of ternary complexes that lead to ubiquitination and subsequent protein degradation.6,7 This makes them a versatile tool for TPD. 

While MGs are difficult to find, X-Chem’s scientists have demonstrated MG selection using a dual target selection protocol and confirmed ternary binding by surface plasmon resonance (SPR), mass photometry and CryoEM. This MG discovery expertise is a game-changer for our partners in the precision medicine field. 

Like PTCs, MGs offer several advantages over traditional small molecule inhibitors. For example, they can target proteins that are difficult or impossible to inhibit directly, and they also offer the potential for sustained target degradation with a single dose.7,8 MGs are also capable of changing protein-protein interactions and interactomes and hold promise for diseases caused by protein misfolding, such as Alzheimer’s and Parkinson’s.6,8 These diseases are notoriously difficult to treat with traditional small molecule inhibitors. Through TPD, however, MGs address the root causes of disease, not just the symptoms. 

The Future of TPD Discovery 

PTCs offer the potential for highly specific protein degradation that hits at the source of disease.6,8 As this field evolves, there is life-changing potential for novel therapeutics across a wide range of indications, including neurodegenerative diseases, cancer, infectious diseases and autoimmune disorders.1,3,7 

Despite the therapeutic potential of TPDs, challenges exist in terms of specificity, stability, biodistribution and penetration of these degrader molecules. Leading-edge DEL technology and rational design, however, are keys to the development of more effective TPD treatments. With our highly advanced proprietary platform, massive libraries and medicinal chemistry expertise, X-Chem will continue to provide unparalleled services that rapidly and safely advance our partners’ programs in the new era of precision medicines.  

Harnessing the Power of TPDs 

Capitalizing on the advantages of TPDs is essential to the development of novel precision medicines that have the potential to change the way devastating and previously difficult-to-drug diseases are treated. DEL technology is playing a significant role in the advancement of TPD-based precision medicines, and there is no sign that will change anytime soon.  

X-Chem’s experience, technology and TPD expertise place us at the forefront of this exciting area of research, and we are well-equipped to continue helping our partners develop highly specific TPD-based candidates. 

Expedite your TPD discovery with the experts at X-Chem. 

References

  1. Burslem, G.M. et al. Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery. Cell, 2020, 181(1), 102-114.
  2. Balchin, D. et al. In vivo aspects of protein folding and quality control. Science, 2016, 353(6294).
  3. Alabi, S.B. et al. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs. JBC REVIEWS, 2021, 296, 100647.
  4. Liu, Z. et al. An overview of PROTACs: a promising drug discovery paradigm. Molecular Biomedicine, 2022, 3(46).
  5. Bond, M.J. et al. Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation. RSC Chem. Biol., 2021, 2, 725-742.
  6. Dong, G. et al. Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery. J. Med. Chem. 2021, 64, 15, 10606–10620.
  7. Sasso, J.M. et al. Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic. Biochemistry, 2023, 62, 3, 601–623.
  8. Li, F. et al. Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein–Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases. Int. J. Mol. Sci. 2022, 23(11), 6206.

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